Chris Emery: Welcome to the Salk Talk podcast. I’m your host Chris Emery. Joining us for this episode of Salk Talk is Shani Stern, a neurophysiologist working in the laboratory of Salk professor Rusty Gage, who’s research focuses on understanding the biological underpinnings of mental diseases such as bipolar disorder and schizophrenia. To learn more about the Salk Institute and it’s research visit www.salk.edu. Welcome Shani.
Shani Stern: Thank you.
Chris Emery: Your career has taken some fascinating twists and turns, let me see if I have this right. You got your undergraduate degree in electrical engineering and then served in the Israeli Defense Forces, then you worked as an electrical engineer for Intel and Motorola for several years, then you earned a doctorate in Physics from the Weizmann Institute in Israel, and now here you are at the Salk Institute studying the brain. Is that the right sequence?
Shani Stern: Yes, pretty much. Most people do it the other way around. First they go to school for a long time and then they work, but my family there are a lot of electrical engineers, and I also thought especially with high school I like math, I like physics, I like computer science, and I thought it would be a good path for me. I learned it, and then I had to serve in the army as all Israeli’s do. I served a little bit more because I was an officer, and then when I sent my CV I got a million offers because electrical engineers in Israel they’re very needed. It was like a golden cage that I was earning a good salary, I didn’t want to leave because it was a good position, but at some point I kind of felt that I knew more than anybody. When I worked for Motorola in speech, I did speech algorithms, and I had nobody that I could learn from and I got a little bored. Then I kind of thought of starting to go back to the academia. I also started being interested in biology, which was not like during high school it didn’t interest me at all. I got more mature, I had children, I started having children, I started to read, it sounded really interesting. I started being interested in biology. I went first to the regular universities and they said, “Ah, you need to make a lot of courses.”
Chris Emery: I see because you were an electrical engineer.
Shani Stern: Yes.
Chris Emery: You didn’t have that background.
Shani Stern: Yes, and then I went to the Weizmann Institute, and they interviewed me and they said, “You know what, we really want you here. Don’t make up anything, just come.” I came and I didn’t make up any courses but I just studied on my own. I started in computer science, I did my masters in computer science in the bioinformatics track, so I just learned the biology. Then during my PhD I really wanted to get even deeper into the biology, even do what lab work, so I joined the lab of Elisha Moses, Professor Elisha Moses who is doing physics but is like neurophysics. When I started in his lab I kind of did more neurophysics like stimulation with electric and magnetic fields, but what interested me a lot was the biology. I kind of started to pull towards disorders, and Elisha was fine with it so that’s how I ended up. I started to collaborate with neuroscience department with Menahem Segal and that’s how I ended up studying brain disorders.
Chris Emery: You mentioned having children. Was there something about that that got you interested in biology?
Shani Stern: First it’s really a miracle, so that changes everybody the first time you have a child, it changes you. I really started to read and once you start to read you realize it’s really interesting. I don’t know if they didn’t teach it well in high school or I was just not mature enough to realize how interesting it was, I don’t know.
Chris Emery: Yes, I have a three year old and it’s amazing to watch a child go from being born to being three and talking and walking and running around.
Shani Stern: Yes, it is amazing.
Chris Emery: You and I actually have something in common because I worked in a lab out of college as neurophysiology technician, so I have a little bit of a head start on maybe some of our listeners as to what that actually means. Could you tell people a little bit about what is neurophysiology and why is it important in neuroscience?
Shani Stern: Yes, so we actually have many techniques for looking at the physiology or electrophysiology, but when you really want to record currents and potentials you go to an old technique, which is the patch clamp, which was invented back in the 70s. You generally record a single cell or two cells, not more, and what you do is you have a pipette with an electrode inside and then it is connected to an amplifier and an A2D, which connects to your computer. What you do is you go very, very close to the cell, you apply small suction, you rupture the membrane, and now you current your fuse with a cytoplasm you can record currents and potentials of the cell. Then just because the resolution is high, you’re really connected, the noise is low, you can record with some protocols, specific types of currents or ion channels. When you study disorders and the changes are usually small because these are functioning organisms, they’re just a little bit different. The changes are going to be small so you need this resolution, you need to measure these small currents, these changes in the small currents to see the differences.
Chris Emery: Your work in the lab most recently is focused on bipolar disorder, which used to be called manic depression in the past but it’s since been renamed. This is a disease that can cause really in terrible disruptions in people’s lives. Do we know what’s actually going on in the brain during these different phases? What’s actually malfunctioning?
Shani Stern: Yes, so that’s where our modeling system comes because it’s hard to record from actual brains. We have the IPS technology.
Chris Emery: Induced pluripotent stem cells.
Shani Stern: Yes, and we can differentiate them into specific types of neurons. We can look at different areas of the brain and see how the neurons react differently. For example, we looked already at several types but the one that we have the most statistics for is the dentate gyrus granule neurons, this is an area in the hippocampus which produces newborn neurons. We see that bipolar neurons are hyperexcitable, they produce more activity and they have sustained activity. For example, if I inject a current for a control cell it will fire and at some point it will just get tired and stop firing, but the bipolar cell can go on and on just firing without any rest.
Chris Emery: The cellular version of mania.
Shani Stern: Yes. Then we’re starting now to do more types of cells, so we have a lot of data from CA3 neurons, it’s also hippocampal neurons. We see, for example, that there only the bipolar patients that respond to lithium have hyperexcitability in the CA3 cells, but the ones that do not respond to lithium do not have hyperexcitability, but their changes, for example, are in the morphology of the cells. They just make huge CA3 cells, the bipolar and nonresponsive cells.
Chris Emery: Lithium it’s the common treatment prescribed for people with bipolar.
Shani Stern: Yes, so usually it’s the drug that psychiatrists would start with. It’s kind of a miracle drug because it helps in both stages, both in the phase of the mania and the phase of the depression. It works well only about 30% of the patients, and then 70% of the patients some of them do not respond at all, some of them respond not well enough, but it’s being prescribed to everybody as the first line of treatment for bipolar disorder.
Chris Emery: I see, even though there’s this fairly large percentage that are non-responsive.
Shani Stern: Yes, so it’s kind of like what the drug that most psychiatrists would think of first associated with bipolar disorder is lithium.
Chris Emery: You just recently published some findings that may help explain why some people respond and some people don’t. Can you tell me a little bit about that?
Shani Stern: Yes, so in the dentate gyrus granule neurons we did the study, we-
Chris Emery: The dentate gyrus is a portion of the brain just to help.
Shani Stern: Yes, of the hippocampus yes.
Chris Emery: Hippocampus yes.
Shani Stern: All the bipolar dentate gyrus granule neurons are hyperexcitable, or on average are hyperexcitable, but we see that they are very different if they come from patients who respond to lithium and patients who do not respond to lithium. The kind of only thing that they share in common is hyperexcitability, but they have very different characteristics or electrophysiological characteristics. As an example, if we look at the spike hike, lithium responders have it higher than the control, statistically significant, but non-responders would have it lower than the control. The spike shape is different, the way that they fire is different. We were able to predict, based on electrophysiological features, whether the patient would respond to lithium. We don’t even treat the cells with lithium, although if we do treat these cells with lithium we see that the lithium responder neurons would decrease hyperexcitability, while the non-responders do not. The way we predicted was not even with lithium because just their intrinsic properties are so different that we didn’t even need to treat with lithium to find out who was going to respond to lithium and who will not. Generally what we do is we had six patients, and three of them are lithium responders, and three of them are non-responders. We take one patient out of the sample, we train model, a base model by the five patients, the electrophysiological features, and then we predict or classify the six according to the model that was built by the five. We do this iteratively, so each time we take a different patient out and this way we can assess the performance of the classifier and we get an error rate which is lower than 8% for prediction.
Chris Emery: Does that mean that there may be ways to look at the neurons or the skin cells of a person with bipolar and actually predict whether they should be even given this treatment or not?
Shani Stern: Yes.
Chris Emery: That’s the idea eventually or hopefully.
Shani Stern: Yes, so right now the method is you take skin cells or blood cells, you make them into induced pluripotent stem cells, then into neurons, and then measure five neurons, that’s all you need, from five neurons, for me as an electrophysiologist it would take me about one and a half hours to measure. From these five neurons you can predict with very high accuracy whether this patient would respond to lithium or not. We’re now trying to make this prediction even more easy just by doing some other methods which might be easier, we’re working on it right now.
Chris Emery: I think you told me before when we were talking that that’s important because there’s a downside to being prescribed these drugs if you’re not going to respond to them in the ideal way.
Shani Stern: Yes, so there are two problems. First is that the patients are not getting the treatment that they should be getting. They’re getting lithium, which does not affect them, and second there are many side effects to lithium, so it’s bad to treat people who will not respond to it with the lithium, so yes.
Chris Emery: You’ve clearly pursued the neurosciences, are there other questions about the brain that are just burning questions for you?
Shani Stern: There are always questions yes. Right now I’m kind of focused on psychiatric disorders kind of this is how … I think that’s the main reason I went back to the academia kind of disorders or disease. Was interesting for me, but yes always also interested in the basic science. Right now as electrophysiologist I’m helping other people in the lab, which sometimes do basic neuroscience, to develop new protocols for other types of cells for example.
Chris Emery: Dr. Gage’s laboratory studies a number of disorders including schizophrenia, are there any connections between bipolar and schizophrenia?
Shani Stern: Yes, so I did a lot of patch clamping from schizophrenia, and generally what we see is that they’re hypoexcitable versus bipolar which are hyperexcitable. If you look at the behavior sometimes they have some similarities, so we’re not sure how this is translated to behavior. The only thing like I did a lot of schizophrenia lines and helping with other people’s projects and their cells are hypoexcitable, which is by the way, most of the disorders are hypoexcitable. I did a lot of down syndrome before, it’s hypoexcitable and autism is hypoexcitable. Usually disorders are hypoexcitable neurons, and kind of bipolar I think it was the only one we saw. I have to make sure in my mind that that is hyperexcitable.
Chris Emery: One thing I’m curious about is because I used to work in a neurophysiology lab, I know that the techniques that I used and this was 20 years ago, the techniques have carried on. Are there any areas of technological development in neurophysiology in recording the electrical activity of neurons at that level that have evolved recently?
Shani Stern: Yes, so there are many methods that are helping a lot like multielectrode arrays and sometimes there are voltage sensitive dyes so you can see or calcium imagining. That has evolved, but still if you want to get resolutions of specific line channels currently the only method is to go and do patch clamp.
Chris Emery: You have four children correct?
Shani Stern: Yes I do.
Chris Emery: Gets me tired just saying it. You have this background in math and engineering. What goes on in your household?
Shani Stern: The first thing that I learned very well was to parallel things, so I make dinner and I help with the homework and I’m folding laundry. Everything is in parallel, done in parallel. Second, yes I teach math, high level math to my children. It started when they were very little and I thought in the preschools they weren’t getting enough, so I kind of started then and it went well so I continued. Now, like everybody studies the math that is a few grades above his level and they’re fine with it usually. Yes, I’m just continuing with it. I think it’s good for them.
Chris Emery: They seem to have an interest in science and math?
Shani Stern: They do, yes I think they do.
Chris Emery: Are there any outliers or do you have a child who’s completely gone off into the arts?
Shani Stern: They like the arts too, so it’s not that they’re only focused on science. It’s just for me it’s harder … I also painted when I was younger, now I don’t have time. I don’t have the time to teach them and the schools here are very good with the art. They’re learning in school and they like the art very much.
Chris Emery: How long were you in the military?
Shani Stern: Three years.
Chris Emery: Three years, did that have any influence on switching from focusing on electrical engineering to biology?
Shani Stern: I don’t think so, but I think that what I did learn just from being an officer was just to parallel everything and to delegate authorities. My children help me a lot. We have one child making breakfast, one child making dinner, we clean the house, everybody cleans together, everybody knows exactly their role and which time they need to do it. Sometimes they complain a little bit but there is no choice so yes.
Chris Emery: The stern household is an efficient operation.
Shani Stern: Yes.
Chris Emery: Run by an engineer and former military lieutenant.
Shani Stern: Exactly.
Chris Emery: Well Shani thank you so much for joining us today.
Shani Stern: Thank you.
Chris Emery: To learn more about the Salk Institute and it’s research visit www.salk.edu.